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Optimal Quality ¹³¹I-Monoclonal Antibodies on High-Dose Labeling in a Large Reaction Volume and Temporarily Coating the Antibody with IODO-GEN

Radionuclide Center Vrije Universiteit and Departments of Obstetrics and Gynecology, Otolaryngology, and Nuclear Medicine/PET Center, University Hospital Vrije Universiteit, Amsterdam, The Netherlands

A novel, facile procedure for efficient coupling of high doses of ¹³¹I to monoclonal antibodies (MAbs) was developed with minimal chemical and radiation damage. Methods: To diminish the radiation and chemical burden during labeling, iodination was performed in a large reaction volume and by temporarily coating the MAb with a minimal amount of IODO-GEN. The MAb was coated by injection of IODO-GEN (dissolved in acetonitrile [MeCN]) into the aqueous MAb solution, and the coating was subsequently removed by addition of ascorbic acid. For chemoprotection before, during, and after PD-10 purification of the ¹³¹I-MAbs, ascorbic acid and human serum albumin were used. The effects of autoradiolysis in the starting ¹³¹I solution were countered by treatment with NaOH and ascorbic acid. For this so-called IODO-GEN–coated MAb method, the sensitive chimeric MAb MOv18 (c-MOv18) and the more robust murine MAbs K928 and E48 were used. The high-dose ¹³¹I-labeled MAbs were characterized for radiochemical purity and MAb integrity by thin-layer chromatography, high-performance liquid chromatography, and sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by phosphor imager quantification. The high-dose ¹³¹I-labeled MAbs were also characterized for immunoreactivity. The radiopharmacokinetics and biodistribution of ¹³¹I-c-MOv18 were analyzed in human tumor–bearing nude mice. For comparison, ¹³¹I-c-MOv18 batches were made using the conventional chloramine-T or IODO-GEN–coated vial method. Results: Conventional high-dose labeling of 5 mg c-MOv18 with 4.4 GBq ¹³¹I resulted in a labeling yield of 60%, a radiochemical purity of 90%, an immunoreactive fraction of 25% (72% being the maximum in the assay used), and the presence of aggregation and degradation products. Using similar amounts of ¹³¹I and MAb in the IODO-GEN–coated MAb method, 85%–89% overall radiochemical yield, at least 99.7% radiochemical purity, and full preservation of MAb integrity and immunoreactivity were achieved. For this labeling, 5 mg MAb were coated with 35 µg IODO-GEN during 3 min in a reaction volume of 6 mL. Also, biodistribution was optimal, and tumor accumulation was superior to that of coinjected ¹²⁵I-c-MOv18 labeled according to the conventional IODO-GEN–coated vial method. Conclusion: A new, facile, high-dose ¹³¹I-labeling method was developed for production of ¹³¹I-labeled MAbs with optimal quality for use in clinical radioimmunotherapy.

Key Words: ¹³¹I labeling • monoclonal antibody MOv18 • IODO-GEN • radioimmunotherapy • immunoreactivity

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